Currently, pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival, new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using metastasis suppressors to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor, KiSS1, is a secreted protein that inhibits metastasis of human melanoma, breast, and ovarian cancer xenograft models. KiSS1 expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSS1, a metastasis suppressor. Preliminary studies indicate that overexpression of KiSS1 greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data, the proposed in vitro and in vivo experiments will evaluate KiSS1 treatment alone or combined with chemotherapy as regards anti-tumor and anti-metastatic efficacy. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSS1 plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSS1 delivery, via construction of an infectivity enhanced, conditionally replication competent KiSS1 adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virus. Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy to examine potential benefits of combination cytotoxic treatment and anti-metastatic therapy on established metastasis and primary tumors in a xenograft model. These studies will be the first to examine KiSS1 treatment on established metastasis and provide vital information on the potential benefits of anti-metastatic treatment for future pancreatic adenocarcinoma patients.